Gallstone disease is a major health problem in the United States. It affects approximately 20% of adult Americans. Gallstones are formed by the precipitation of insoluble bile constituents: cholesterol, polymerized bilirubin, bile pigments, calcium salts, and proteins. Gallstones are classified into cholesterol, black pigment, and brown pigment stones. Cholesterol stones are most frequent in industrialized societies.
Black pigment stones occur in patients with chronic hemolytic disorders, and brown pigment stones are associated with impaction in the biliary tract. These stones are more prevalent than cholesterol stones in the Far East. Cholesterol stones may be pure, large (>2.5 cm), solitary or mixed (>70% cholesterol), multiple, smooth, and faceted. Black and brown stones contain less than 25% cholesterol and are multiple and irregular. They contain polymerized bilirubin and calcium salts (bilirubinate, phosphate, and fatty acids). All types of gallstones may become calcified. The calcification is usually central in pigment stones and peripheral in cholesterol stones.
Pigment stones (black and brown)
Epidemiology. Clinically, black pigment stones are more prevalent in three major settings: hemolytic states, cirrhosis, and the elderly. In the United States, approximately 30% of gallstones are pigment (mostly black) stones. The incidence is age-dependent: pigment stones are more common in the sixth and seventh decades. In Asia, biliary tract parasitism with Clonorchis sinensis and Ascaris lumbricoides, biliary ductal stasis, and chronic or repeated spasm at the sphincter of Oddi as a result of widespread use of opium may contribute to the increased prevalence (approximately 70%) of brown pigment cholelithiasis.
The pathogenesis of black pigment stone formation is not clear; however, there seems to be an increased concentration of the insoluble, unconjugated bilirubin and poorly soluble bilirubin monoglucuronide in the bile of these patients. Abnormal motor function of the gallbladder and reduced bile salt concentration may also contribute to the pathogenesis. Infections with organisms such as Escherichia coli reduce biliary pH and deconjugate bilirubin glucuronide, which may create a nidus for gallstone formation.
- Heredity. The prevalence of cholesterol gallstones varies in different populations. There is a strong correlation between the percentage of cholesterol saturation of gallbladder bile and gallstone formation, as in Pima Indian women in whom the prevalence reaches 80%. Thus hereditary mechanisms are important.
- Age. Gallstones may be found at all ages, but the incidence increases with age.
- Gender. Women, starting at puberty, have a two to three times greater risk of developing gallstones compared to men.
- Pregnancy. Supersaturation of bile with impaired gallbladder emptying during pregnancy due to an increase of estriol, progesterone, and other sex hormone levels increases the incidence of cholelithiasis.
- Use of exogenous estrogens. There is increased cholelithiasis among users of exogenous estrogens and progesterone, as in birth control pills and in postmenopausal estrogen replacement. The condition could be secondary to gallbladder stasis induced by these hormones and to reduced bile flow and altered lipid composition of bile.
- Diabetes. The increased prevalence of cholelithiasis in diabetes is largely due to obesity and increased biliary cholesterol secretion.
- Obesity. The bile of obese people is more lithogenic due to excessive cholesterol secretion caused by increased cholesterol synthesis.
- Rapid weight loss. Regardless of the method of weight loss, up to 25% of patients who lose weight rapidly will develop symptomatic gallstones. With weight loss, cholesterol is mobilized from peripheral adipose tissue and secretes into bile leading to cholesterol supersaturation. Also, the stimulus for gallbladder contraction from dietary fat is diminished leading to gallbladder stasis. Weight fluctuation is also a risk factor for gallstones.
Patients with type I and intravenous hyperlipidemia have a high risk of cholesterol gallstone formation.
Cystic fibrosis and pancreatic insufficiency. Malabsorption of bile salts decreases the bile salt pool and increases the lithogenicity of bile, leading to cholelithiasis.
Ileal disease, bypass, or resection
Extensive disease of the distal small intestine as in Crohn’s disease, or surgical resection of the distal ileum impairs bile salt resorption and predisposes to gallstone formation due to decreased bile acid pool.
- Drugs. Clofibrate used in the treatment of hyperlipidemia decreases serum cholesterol by inhibiting cholesterol synthesis. This stimulates tissue mobilization and increases cholesterol secretion into bile. Bile becomes more lithogenic, leading to cholelithiasis. The somatostatin analog octreotide predisposes to gallstone formation by inducing gallbladder stasis.
- Diet. A high-calorie diet, refined carbohydrates, and diets high in polyunsaturated fatty acids predispose to cholelithiasis. Increased dietary fiber seems to decrease the risk of cholelithiasis. Weight-reduction diets with severe caloric restriction leading to rapid weight loss also may result in cholelithiasis.
- Genetic factors. The prevalence of gallstones is highest in the American Indian tribes, especially the Pima Indians of Arizona. By the age of 30, 80% of Pima women have gallstones. There is also a high prevalence of gallstones in Chile. In addition to genetic factors, it is thought that this high prevalence in Chile is due partly to the high intake of beans, which adversely affects biliary cholesterol saturation. Gallstones are more common in first-degree relatives of patients with gallstones than in the general population.
Spinal injury, especially high spinal section, is associated with a high incidence of gallstones, probably secondary to gallbladder stasis.
Total parenteral nutrition promotes gallbladder stasis and the formation of sludge and gallstones with prolonged use.
Truncal vagotomy may be a risk factor for cholelithiasis secondary to decreased gallbladder motility.
Cholesterol gallstone formation.
The first step in the formation of gallstones is the secretion by the liver of bile supersaturated with cholesterol. Cholesterol in dilute hepatic bile is transported in spherical vesicles of phospholipid and cholesterol into the biliary tract and the gallbladder. Hepatic bile is concentrated in the gallbladder.
The second step in gallstone formation is crystallization. The precipitation of cholesterol crystals initiates the formation of gallstones. When the gallbladder bile becomes abnormally supersaturated with cholesterol, nucleation, flocculation, and precipitation of cholesterol crystals occur, leading to the initiation of gallstone formation. The excessive presence of promoters of crystallization and relative deficiency of inhibitors of crystallization are also thought to be important in the initiation of nucleation and crystal formation. The promoters and inhibitors are most likely proteins such as mucous glycoprotein. The growth of the crystals to macroscopic stones is further facilitated by the gallbladder mucus.
Patients who have cholesterol gallstones may have defects leading to the production of abnormally supersaturated bile due to an absolute increase in the secretory rate of biliary cholesterol or an absolute decrease in the secretory rate of biliary bile salts, lecithin, and phospholipids. Changes in the concentration of one of the key promoters of crystallization, mucous glycoprotein, are mediated by mucosal prostaglandins. Aspirin and nonsteroidal anti-inflammatory drugs, by decreasing PG synthesis, also prevent microcrystal and gallstone formation, especially in obese people undergoing weight reduction through dieting.
Gallbladder motor dysfunction and stasis also contribute to gallstone formation and may be a primary phenomenon.
Clinical presentation. Long-term studies have shown that at least one half of the individuals with gallstones remain asymptomatic, one third experience severe symptoms, and one fifth experience serious complications.
The complications of cholelithiasis include the following:
- Cystic duct obstruction, leading to Colic.
- Acute cholecystitis.
- Cholangitis, sepsis.
- Perforation, peritonitis.
- Fistulization, gallstone ileus.
- Choledocholithiasis, which may cause
- Obstructive jaundice.
- Cholangitis, sepsis.
- Acute pancreatitis.
- Stricture formation.
There is some evidence to suggest that gallstones and chronic cholecystitis also may predispose to carcinoma of the gallbladder.
Dyspeptic symptoms such as heartburn, fat intolerance, and increased «gas» (bloating, flatulence, and belching) are not symptoms specific to gallbladder disease. Biliary colic is pain arising from a distended gallbladder due to obstruction of the cystic duct with a gallstone. Commonly, the «attacks» follow heavy meals. The pain is felt mostly in the right upper quadrant and may radiate to the epigastrium, back, or shoulder. It may be mild or severe, lasts 1 to 6 hours, and usually is accompanied by nausea and vomiting. At times, when the cystic duct obstruction is transient, biliary colic is relieved spontaneously. However, prolonged cystic duct obstruction with a gallstone usually results in acute cholecystitis, cholangitis, and their complications.
Both complications and mortality from gallstones increase with age and with passage of time. The first attack may be severe, especially in the elderly and patients with other serious illness. Because the mortality for these patients from complications of gallstones may be as high as 15% to 20%, elective surgery should be considered when asymptomatic gallstones are found. Surgery is also recommended for patients with symptoms or complications of cholelithiasis.
Other causes of severe upper abdominal pain need tobe considered in the differential diagnosis of biliary colic. These causes include acute myocardial infarction, ruptured aortic aneurysm, perforated peptic ulcer, pneumonia, pneumothorax, pleurisy, intestinal obstruction, intestinal ischemia, pancreatitis, and renal colic.
The demonstration of gallstones by ultrasound is currently the best diagnostic test, having the highest sensitivity (90%-95%) and specificity (98%). An oral cholecystogram may also demonstrate gallstones as well as gallbladder contractile function after ingestion of fat; however, this test is not as sensitive as ultrasound. Computed tomography scan of the gallbladder is much more sensitive than conventional radiography in detecting gallstone calcium. However, ultrasound is more sensitive than computed tomography in detecting gallbladder sludge and stones.
Endoscopic retrograde cholangiopancreatography is useful in identifying common bile duct stones. It is not specific for the diagnosis of gallbladder stones.
Magnetic resonance cholangiopancreatography is a noninvasive method to screen for common bile duct stones as well as for strictures and cystic anomalies of the common bile duct and bile duct dilatation. The reported sensitivity is 70% to 100% and specificity is 80% to 100%.
Management of symptomatic but uncomplicated gallstone disease
The immediate treatment of biliary colic is symptomatic. Pain relief is usually achieved with narcotic analgesics, excluding morphine, and antiemetics.
Laparoscopic cholecystectomy is the recommended treatment for long- term management. If choledocholithiasis is suspected, preoperative endoscopic retrograde cholangiopancreatography with sphincterotomy or intraoperative cholangiography may be necessary. Open cholecystectomy is reserved for patients who have contraindications to the laparoscopic procedure. In the average patient, the mortality of elective cholecystectomy is less than 1%. The risk increases in patients with diabetes, renal insufficiency, cardiovascular disease, respiratory disease, and cirrhosis of the liver.
Extracorporeal shock-wave lithotripsy is not currently used in the United States for uncomplicated gallbladder stones. In centers where Extracorporeal shock-wave lithotripsy is available it may be used for problematic common bile duct stones not cleared by endoscopic retrograde cholangiopancreatography. Extracorporeal shock-wave lithotripsy in combination with oral bile acid therapy has been used for patients who are not surgical candidates and who have single or small cholesterol gallstones and a functioning gallbladder.
Gallstones are localized by three-dimensional ultrasound, then extracorporeal shock waves are focused and fired on the gallstones and fragmentation is achieved. Up to three sessions may be needed to achieve fragmentation of the gallstones into pieces smaller than 3 mm. It is expected that these fragments pass spontaneously into the duodenum or dissolve by oral bile acids. Oral bile acid therapy may need to be continued for several months. Approximately 20% of patients develop biliary colic and 25% subsequently undergo cholecystectomy. Other side effects include pancreatitis (1%), local pain, petechia and bruising, and microscopic hematuria.
Contact solvent gallstone dissolution involves direct introduction into the gallbladder of cholesterol solvents such as methyltert-butyl ether and similar compounds, with or without adjuvants for noncholesterol material such as EDTA and N- acetylcysteine, through percutaneous transhepatic catheters or by endoscopic retrograde cannulation of the cystic duct. This is a rapid (1-15 hours) and effective procedure during which the gallstones disintegrate and fragment and are expected to be suctioned out via the catheters used or placed into the biliary tract. However, 36% to 67% of patients are left with incompletely dissolved residual stones smaller than 5 mm in diameter. With adjuvant oral bile acid therapy, many of these stones may dissolve completely.
Gallstone dissolution with oral bile acid therapy is based on the theory that cholesterol stones should dissolve in bile rendered unsaturated with respect to cholesterol by increasing the concentration of bile salts. Gallstone clearance may not depend completely on stone dissolution. Cholesterol-rich stones can disintegrate as they dissolve, and the resultant fragments might pass out of the gallbladder in the bile via the cystic duct and into the common bile duct and duodenum.
The first bile acid used orally was chenodeoxycholic acid.
Chenodeoxycholic acid decreases the cholesterol saturation of bile by lowering cholesterol secretion, thus bringing about a gradual dissolution of cholesterol stones. In a controlled trial using 12 to 15 mg/kg per day (approximately 1 g daily), the stones dissolved in 40% to 60% of the selected patients during 2 years of continuous therapy.
Contraindications. Dissolution therapy is contraindicated in the presence of any of the following:
- Pigment stones.
- Calcified stones.
- Stones larger than 1.5 to 2.0 cm.
- Multiple stones.
- Nonopacifying gallbladder on oral cholecystogram.
- Pregnancy or women who may become pregnant.
- Concomitant liver disease.
- Severe symptoms.
- Nonresponders by oral cystography after 9 months of therapy.
- Poor patient compliance.
The most common side effect is secretory diarrhea induced by the bile acid in the colon. Occasionally, gallstones become small enough during therapy to pass into and obstruct the cystic or common bile duct, resulting in inflammation. Minor liver enzyme elevations may occur in 7% of the patients, without any significant structural changes in liver histology. There may be a modest rise in plasma and low-density lipoprotein cholesterol.
Maintenance of therapy
Сhenodeoxycholic acid therapy needs to be maintained indefinitely in all patients because the bile reverts to its previous supersaturated state in 1 to 3 weeks after cessation of the therapy, and stones recur within 6 to 48 months.
Ursodeoxycholic acid is more potent than chenodeoxycholic acid in lowering biliary cholesterol secretion and saturation. It also has fewer side effects. It does not affect the serum low-density lipoprotein levels or liver chemistry tests. A Ursodeoxycholic acid dosage of 10 mg/kg per day is optimal and equivalent to a chenodeoxycholic acid dosage of 15 mg/kg per day. In some patients, stone rim calcifications may occur and limit dissolution.
The combination of Ursodeoxycholic acid and chenodeoxycholic acid is at least as effective and free of side effects as monotherapy with Ursodeoxycholic acid and is less expensive. The dosage of chenodeoxycholic acid is reduced to 7.5 mg/kg per day, and Ursodeoxycholic acid is used at a dosage of 5 mg/kg per day.